NSAIDs are the most widely used medications in the world. Their use can start as early as infancy for treating pain and fever and can continue into senescence where they are standard therapy for treating osteoarthritis and other musculoskeletal conditions (1). The mechanism for both the therapeutic anti-inflammatory, analgesic and antipyretic actions as well as the undesired side-effects of non-steroidal anti-inflammatory drugs (NSAIDs) on the stomach and kidneys is primarily mediated through their inhibition of cyclooxygenase (COX), the rate-limiting enzyme in the synthesis of prostaglandins. COX exists in two isoforms, known as COX-1 and COX-2, which have different structures and functions. COX-1 is involved in a number of reactions, including the production of prostacyclin, which is both antithrombogenic and, in the gastric mucosa, cytoprotective. COX-2 is believed to be induced by inflammatory mediators and has a pathophysiological role in inflammation. The beneficial anti-inflammatory effects of the NSAIDs are believed to be mediated by the inhibition of COX-2, while the inhibition of COX-1 produces the undesirable gastrointestinal side effects. A more detailed review of these mechanisms and their impact on the use of NSAIDs is provided by Meek et al. (2).
The first generation NSAIDs which were successfully marketed as both prescription and over-the-counter (OTC) medications are relatively non-specific for COX-2 and also produce significant inhibition of COX-1, thereby decreasing its protective effect on the gastrointestinal mucosa. NSAID therapy reportedly is associated with upper gastrointestinal (GI) symptoms in 25% of patients, causes ulcers or erosions in 40% of patients, increases the risk of ulcer bleeding or perforation three- to fourfold, and increases the rate of hospitalization or death from GI complications fivefold. NSAID therapy is also associated with lower GI complications, i.e., 10-15% of NSAID users experience diarrhea. Furthermore, the risk of intestinal ulceration, erosion, perforation, and stricture formation increases in patients taking NSAIDs. Treatment and prevention of these adverse GI effects dramatically increase the cost of NSAID therapy (2). It has been estimated (3) that oral NSAIDs are responsible for over 100,000 hospitalizations due to gastrointestinal bleeding and more than 16,000 deaths per year, resulting in hospitalization costs of $2 billion annually.
As a result of these shortcomings a large body of research has been directed towards finding NSAIDs which would be specific for COX-2. The result of these efforts was the introduction in the late 1990's of a number of compounds with more specific COX-2 inhibition such as rofecoxib (Vioxx®), celecoxib (Celebrex®), and valdecoxib (Bextra®). Unfortunately, the long-term use of these agents has demonstrated serious cardiovascular consequences such as myocardial infarction and stroke. These adverse events prompted Merck to recall Vioxx® from the US market on Sep. 30, 2004 (4). Shortly thereafter, on Apr. 7, 2005, Bextra® was also withdrawn from the US and European Union (EU) markets (5). These events were significant as Celebrex® with $3.3 billion in sales in 2004, and Bextra® with $1.3 billion in 2004 sales, were among Pfizer's top selling products (5). The FDA also requested that manufacturers of all NSAIDs make labeling changes to their products so that the package inserts include a “boxed warning” highlighting the potential for increased risk of cardiovascular events and the well described, serious, potentially life-threatening gastrointestinal bleeding associated with their use. The Celebrex® labeling was to contain, in addition to the general labeling that would apply to all NSAIDs, safety data from long-term treatment trials with celecoxib. A meta-analysis of data regarding NSAID use in 15 countries representing high-, medium-, and low-incomes was recently performed (6). This study suggests that, among traditional NSAIDS, oral diclofenac may carry the highest risk of adverse cardiovascular (CV) events and death (6). The study concluded that oral diclofenac use carried a CV risk equivalent to Vioxx®, in at-risk populations. The researchers suggested that diclofenac should be removed from national essential medicines lists (EMLs) and that it's marketing authorization should be revoked globally. Others (7,8) who commented on this article exhibited both dismay and great concern as to why diclofenac continues to be the most widely recommended NSAID in the world (found on the EML of 74 countries) while a potentially safer alternative such as naproxen is found on the EML of only 27 countries.
These examples illustrate that there is a substantial need for alternate delivery systems for NSAIDs that can minimize these life-threatening adverse events.